Integrins are receptors that can mediate the attachment between a cell and the tissues surrounding thereof, wherein the tissues can be, for example, other cells or the extracellular matrix (ECM). Integrins are also involved in cell signaling and the regulation of cell cycle, shape, and motility. It is now known that activation of integrins allows for bidirectional (outside-in and inside-out) transmission of mechanical and biochemical signals across the plasma membrane, leading to a cooperative regulation of cell functions, including adhesion, migration, growth, and differentiation. Thus, integrins transduce information from the ECM to the cell as well as reveal the status of the cell to the outside so that the cell can make rapid and flexible responses to changes in the environment.
Integrins are transmembrane proteins and have various types, and a cell may have more than one type of integrins on its cell membrane. Specifically, the integrins located on the cell membrane are in the heterodimer form and have an α and a β submits which are bound by non-covalent bond. For example, αVβ3 integrins are formed by an αV and a β3 integrin submits.
Integrins on the cell membrane may interact with the epidermal growth factor receptor (EGFR) and therefore influence the growth of cancer cell and cause the resistance to chemotherapy for cancer. Regarding usage of integrins for the research and clinical treatment of cancer, antibody against integrins is applied and antagonize the receptor of integrins so as to inhibit growths of cells, e.g. vascular endothelial cell, in which integrins are highly expressed or cancer cells. On the other hand, expression of integrins family may need to be raised for the repair and/or regeneration of central nervous system. Recently, integrins are taken as the target for the research and clinical treatment of some diseases such as cancer, multiple sclerosis, Crohn's disease, psoriasis, rheumatoid arthritis, acute coronary syndromes, etc.
In 2008, the market of treatment for the above-mentioned diseases was estimated as more than one billion US dollars. Now the products, being available on the market, for the treatment of those diseases include ReoPro (Abciximab) and Tysabri (Natalizumab). ReoPro is a humanized monoclonal antibody that blocks the function of β3 integrin and is applied to clinical treatment of percutaneous transluminal coronary angioplasty (PTCA) for unstable angina. Tysabri, a monoclonal antibody, blocks the function of α4 integrin and is used for the monotherapy of relapsing-remitting multiple sclerosis. However, the inhibitor against single integrin molecule, such as α4 or β3, does not provide good treatment effects. Moreover, those antibody drugs are expansive, probably induce allergy caused by heterologous protein and may have lost efficacy due to host's immunoreaction.
Furthermore, epithelial membrane protein-2 (EMP2) is a hydrophobic membrane protein and the study and clinical application therefor are limited in the diseases relating to the pathway regulated by female hormones such as endometrial cancer. However, the relations between EMP2 and other proteins or diseases are not clearly demonstrated.
Employing experiments and researches full-heartily and persistently, the applicant finally conceived regulator, pharmaceutical composition encompassing the regulator and application thereof.